Serum Albumin Affects the Time-to-treatment Failure of Alectinib: A Multicenter Retrospective Study.

BACKGROUND/AIM: Alectinib is recommended for anaplastic lymphoma kinase fusion gene-positive non-small cell lung cancer. We have experienced early alectinib discontinuation due to disease progression and adverse effects in real world. Because alectinib has a high protein-binding rate of >99%, low serum albumin may increase the concentration of free drug and affect efficacy and adverse events. However, no association between serum albumin and the clinical impact of alectinib has been reported. The purpose of this study was to determine the effect of serum albumin on time-to-treatment failure (TTF) in alectinib. PATIENTS AND METHODS: Fifty-six patients who were admitted to four hospitals (National Hospital Organization Hokkaido Cancer Center, Sapporo Minami-Sanjo Hospital, KKR Sapporo Medical Center, Otaru General Hospital) between October 2014 and September 2020 were retrospectively evaluated to identify those treated with alectinib. RESULTS: The multivariate analysis showed that the risk of discontinuation was significantly higher with serum albumin <3.6 g/dl compared to ≥3.6 g/dl at the start of alectinib administration (hazard ratio=3.00; 95% confidence interval=1.36-6.66; p<0.01). On Kaplan-Meier curves, TTF for serum albumin <3.6 was significantly shorter than that for ≥3.6. (median TTF: 12.1 months vs. not reach, p<0.01). CONCLUSION: To the best of our knowledge, this study is the first to report that serum albumin <3.6 g/dl at alectinib induction is associated with poor TTF. Low serum albumin is a poor prognostic factor in cancer patients. Thus, serum albumin levels must be measured before treatment.

[Association of Geriatric Nutritional Risk Index with Adverse Events and Time to Treatment Failure in Malignant Lymphoma Patients Treated with(R-)EPOCH].

To date, there are no reports that examine the relationship between geriatric nutritional risk index(GNRI)at the start of chemotherapy for malignant lymphoma and adverse effects. In this study, we investigated the relationship between GNRI at the start of chemotherapy and the incidence of side effects and time to treatment failure(TTF)in(R-)EPOCH-treated patients with relapsed or refractory malignant lymphoma. A significant difference in the incidence of Grade 3 or higher thrombocytopenia was observed between high and low GNRI groups(p=0.043). The GNRI may be an indicator of hematologic toxicity in malignant lymphoma patients treated with(R-)EPOCH. There was a statistically significant difference in TTF between the high and low GNRI groups(p=0.025), suggesting that nutritional status at the start of(R-)EPOCH may affect treatment continuation.

Association between Area under the Curve Estimated from Carboplatin Dose and Incidence of Severe Thrombocytopenia in Patients with Non-Hodgkin's Lymphoma on DeVIC Therapy.

BACKGROUND: The degrees of adverse effects with carboplatin (CBDCA) are influenced by interindividual differences in the area under the curve (AUC), whereas renal function is not considered in the CBDCA dose design for dexamethasone, etoposide, ifosfamide, and CBDCA (DeVIC) therapy. We conducted this study to evaluate the association between the AUC and incidence of severe thrombocytopenia in patients treated with DeVIC with or without rituximab (DeVIC ± R). METHODS: We retrospectively analyzed clinical data for 36 patients with non-Hodgkin's lymphoma who received DeVIC ± R between May 2013 and January 2021 at the National Hospital Organization Hokkaido Cancer Center. The AUC of CBDCA (AUCactual) was calculated backward using a variant of the Calvert formula. RESULTS: The median AUCactual was 4.6 (interquartile range: 4.3-5.3) min mg/mL and AUCactual was negatively correlated with the nadir platelet count (r = -0.45; P < 0.01). Multivariate analysis showed that AUCactual ≥ 4.3 versus < 4.3 was an independent factor predictive of severe thrombocytopenia (odds ratio: 19.3, and 95% confidence interval: 1.45-258; P = 0.02). CONCLUSION: This study suggests that the CBDCA dosing design considering renal function can reduce the risk of severe thrombocytopenia in DeVIC ± R therapy.

The Concentration of 8-Hydroxy-2'-Deoxyguanosine in Plasma During the Menstrual Cycle in Young Japanese Women.

Background: The exact pathophysiology of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) is still unknown. This study aimed to investigate the concentration of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in plasma in relation to the menstrual cycle and the severity of premenstrual symptoms in young Japanese women. Methods: The study included 21 healthy Japanese women 19-24 years of age. Fourteen women had no or mild PMS [PMS (-)], while five women had moderate to severe PMS and two women exhibited PMDD [PMS (+)]. The concentration of 8-OHdG in plasma was measured by means of high-performance liquid chromatography-electrochemical detector. The Center for Epidemiologic Studies Depression (CES-D) scale was used to evaluate the depressive tendency. Results: The concentration of 8-OHdG before menstruation was significantly higher than that after menstruation in total subjects (p = 0.04). In the PMS (+) group, the 8-OHdG concentration before menstruation was higher than that after menstruation (p = 0.02). Moreover, the PMS (+) group showed a higher 8-OHdG concentration compared with the PMS (-) group before menstruation (p < 0.01), as well as higher CES-D scores compared with the PMS (-) group both before and after menstruation (p < 0.01). Conclusions: These results suggested that the oxidation of DNA occurred before menstruation in PMS. The depression was associated with PMS symptoms both before and after menstruation in patients with PMS. Oxidation of DNA due to oxidative stress and depression in PMS patients may be involved in the pathogenesis of PMS. Clinical Trial Registration number 15-02-011.

Methotrexate mediates the integrity of intestinal stem cells partly through nitric oxide-dependent Wnt/ß-catenin signaling in methotrexate-induced rat ileal mucositis.

This study aimed to elucidate the role of nitric oxide (NO) in intestinal stem cells in methotrexate-induced ileal mucositis in rats. Methotrexate induced the mRNA expressions of the Wnt/ß-catenin target genes Wnt3a, Sox9, and Lgr5 and the Wnt-antagonist gene sFRP-1 and the protein expressions of Lgr5 and sFRP-1. Methotrexate also induced Lgr5+ cells and lysozyme+ cells. A non-selective NO inhibitor inhibited the methotrexate induction of Wnt/ß-catenin target genes and Lgr5+ cells but enhanced that of sFRP-1 expression. Thus, methotrexate mediates the integrity of intestinal stem cells partly through NO-dependent Wnt/ß-catenin signaling and may enhance tolerability to methotrexate-induced injury.

Effect of Systemic Corticosteroid Therapy on the Efficacy and Safety of Nivolumab in the Treatment of Non-Small-Cell Lung Cancer.

INTRODUCTION: Corticosteroids are used to treat immune-related adverse events (irAEs) associated with nivolumab. However, patients with non-small-cell lung cancer who are administered corticosteroids before the initiation of nivolumab treatment are commonly excluded from clinical trials. The appropriate timing for corticosteroid administration in relation to nivolumab treatment, effects of corticosteroids on the efficacy of nivolumab, and resulting adverse events are not clearly understood. In this study, the effects of differences in the timing of corticosteroid administration on nivolumab efficacy and the resulting adverse events were examined. METHODS: A retrospective study was conducted with 109 patients who were treated with nivolumab at Sapporo Minami-Sanjo Hospital between December 2015 and March 2018. RESULTS: Of the 109 patients treated with nivolumab, 12 patients were administered corticosteroids before the first cycle of nivolumab (pre-CS), and 33 patients were administered corticosteroids after the first cycle of nivolumab (post-CS). These 2 groups were compared with the control group comprising 64 patients who were not administered corticosteroids (non-CS). The objective response rate in the post-CS group was significantly higher than that in the non-CS group, and the disease control rate in the pre-CS group was significantly lower than that in the non-CS group. The overall survival time and progression-free survival time in the pre-CS group were significantly shorter than those observed in the non-CS group; however, these did not differ from those in the post-CS group. CONCLUSIONS: These results suggest that corticosteroids administered to patients with non-small-cell lung cancer after initiation of nivolumab treatment did not affect the disease prognosis. Thus, corticosteroids can be administered immediately for rapid treatment of irAEs.

Epalrestat suppresses cadmium-induced cytotoxicity through Nrf2 in endothelial cells.

Cadmium (Cd) is an industrial and environmental pollutant that targets the vascular endothelium. The vascular system is critically affected by Cd toxicity. Recent studies have indicated an association between Cd and vascular diseases, although the mechanisms of Cd implications in vascular diseases are not clear. The purpose of the present study was to determine whether epalrestat (EPS), which is used for the treatment of diabetic neuropathy, protects against Cd-induced cytotoxicity in bovine aortic endothelial cells (BAECs). In the present study, the effects of EPS at near-plasma concentration were examined on Cd-induced cytotoxicity in BAECs. Cd-induced cytotoxicity was suppressed by pretreatment with EPS. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that serves a role in regulating the expression of glutamate cysteine ligase, the rate-limiting enzyme in glutathione (GSH) synthesis. In a previous study, EPS was demonstrated to increase GSH levels in BAECs in association with the Nrf2 pathway. In the present study, EPS increased GSH levels in BAECs exposed to Cd. The protective ability of EPS against the Cd-induced cytotoxicity disappeared following Nrf2 small interfering RNA transfection. In addition, EPS affected the intracellular levels of Cd, Cd transporter ZIP8 and metallothionein. To the best of our knowledge, the current study demonstrated, for the first time, that EPS suppresses Cd-induced cytotoxicity in BAECs. The upregulation of GSH may be associated with the suppression of Cd-induced cytotoxicity by EPS. From these findings, it may be proposed that the regulation of GSH, ZIP8 and metallothionein by EPS is a promising therapeutic approach to prevent Cd-induced toxicity.

Plasma Interleukin-10 Levels Are Altered in Women with Severe Premenstrual Syndrome: A Preliminary Study.

Background: The precise pathophysiology of premenstrual syndrome (PMS) is unknown, and chronic inflammation has been implicated in PMS. However, inflammatory markers, including cytokines and C-reactive protein (CRP), have not been investigated before and after menstruation in relation to PMS among the same participants. This study investigated whether the plasma levels of tumor necrosis factor-α, interleukin (IL)-6, IL-10, and CRP are related to PMS. Methods: The study included 21 healthy Japanese women (aged 19-24 years) with a regular menstrual cycle. Inflammatory marker levels in plasma were determined using enzyme-linked immunosorbent assay. In addition, the level of depressiveness was assessed using the Center for Epidemiologic Studies Depression (CES-D) scale. Results: Of the 21 women, 7 were considered to have moderate-to-severe PMS (PMS [+] group) and 14 were considered to have no or mild PMS (PMS [-]), and none of the participants had premenstrual dysphoric disorder. The IL-10 levels were significantly lower before than after menstruation in the PMS (-) group. The IL-10 levels before menstruation were significantly higher in the PMS (+) group than in the PMS (-) group. Other markers did not show relevant differences between the groups. The CES-D scores were higher in the PMS (+) group than in the PMS (-) group both before and after menstruation. There were positive correlations between the CES-D scores and IL-6 levels before menstruation and the CES-D scores and IL-10 levels after menstruation. Conclusions: The IL-10 levels before menstruation were higher in women with PMS than in those without PMS, and these levels might be related to PMS.

Epalrestat Upregulates Heme Oxygenase-1, Superoxide Dismutase, and Catalase in Cells of the Nervous System.

Heme oxygenase (HO)-1 has potent antioxidant and anti-inflammatory functions. Recent studies have shown that the upregulation of HO-1 is beneficial to counteract neuroinflammation, making HO-1 a new therapeutic target for neurological diseases. We have reported that epalrestat (EPS), which is currently used for the treatment of diabetic neuropathy, increases HO-1 levels through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) in bovine aortic endothelial cells. In this study, we tested the hypothesis that EPS upregulates HO-1 via Nrf2 activation in the component cells of the nervous system, by using rat Schwann cells and human SH-SY5Y cells. Treatment of Schwann cells with EPS at near-plasma concentration led to a dramatic increase in HO-1 levels. Nrf2 knockdown by small interfering RNA (siRNA) suppressed the EPS-induced HO-1 expression. EPS did not promote the intracellular accumulation of free ferrous ion and reactive oxygen species, by increasing ferritin via Nrf2 during HO-1 induction. Moreover, EPS stimulated the expression of superoxide dismutase 1 and catalase, which also are Nrf2 target gene products. It also markedly increased HO-1 levels in SH-SY5Y cells through the activation of Nrf2. We demonstrated for the first time that EPS upregulates HO-1, superoxide dismutase, and catalase by activating Nrf2. We suggest that EPS has the potential to prevent several neurological diseases.

Glycolaldehyde induces endoplasmic reticulum stress and apoptosis in Schwann cells.

Schwann cell injury is caused by diabetic neuropathy. The apoptosis of Schwann cells plays a pivotal role in diabetic nerve dysfunction. Glycolaldehyde is a precursor of advanced glycation end products that contribute to the pathogenesis of diabetic neuropathy. In this study, we examined whether glycolaldehyde induces endoplasmic reticulum (ER) stress and apoptosis in rat Schwann cells. Schwann cells treated with 500 µM glycolaldehyde showed morphological changes characteristic of apoptosis. Glycolaldehyde activated apoptotic signals, such as caspase-3 and caspase-8. Furthermore, it induced ER stress response involving RNA-dependent protein kinase-like ER kinase (PERK), inositol-requiring ER-to-nucleus signal kinase 1α (IRE1α), and eukaryotic initiation factor 2α (eIF2α). In addition, glycolaldehyde activated CCAAT/enhancer-binding homologous protein (CHOP), an ER stress response factor crucial to executing apoptosis. Knockdown of nuclear factor E2-related factor 2 (Nrf2), which is involved in the promotion of cell survival following ER stress, enhanced glycolaldehyde-induced cytotoxicity, indicating that Nrf2 plays a protective role in the cytotoxicity caused by glycolaldehyde. Taken together, these findings indicate that glycolaldehyde is capable of inducing apoptosis and ER stress in Schwann cells. The ER stress induced by glycolaldehyde may trigger the glycolaldehyde-induced apoptosis in Schwann cells. This study demonstrated for the first time that glycolaldehyde induced ER stress.

Epalrestat increases glutathione, thioredoxin, and heme oxygenase-1 by stimulating Nrf2 pathway in endothelial cells.

Epalrestat (EPS) is the only aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy. Recently, we found that EPS at near-plasma concentration increases the intracellular levels of glutathione (GSH) in rat Schwann cells. GSH plays a crucial role in protecting endothelial cells from oxidative stress, thereby preventing vascular diseases. Here we show that EPS increases GSH levels in not only Schwann cells but also endothelial cells. Treatment of bovine aortic endothelial cells (BAECs), an in vitro model of the vascular endothelium, with EPS caused a dramatic increase in intracellular GSH levels. This was concomitant with the up-regulation of glutamate cysteine ligase, an enzyme catalyzing the first and rate-limiting step in de novo GSH synthesis. Moreover, EPS stimulated the expression of thioredoxin and heme oxygenase-1, which have important redox regulatory functions in endothelial cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates the expression of antioxidant genes. EPS increased nuclear Nrf2 levels in BAECs. Nrf2 knockdown by siRNA suppressed the EPS-induced glutamate cysteine ligase, thioredoxin-1, and heme oxygenase-1 expression. Interestingly, LY294002, an inhibitor of phosphatidylinositol 3-kinase, abolished the EPS-stimulated GSH synthesis, suggesting that the kinase is associated with Nrf2 activation induced by EPS. Furthermore, EPS reduced the cytotoxicity induced by H2O2 and tert-butylhydroperoxide, indicating that EPS plays a role in protecting cells from oxidative stress. Taken together, the results provide evidence that EPS exerts new beneficial effects on endothelial cells by increasing GSH, thioredoxin, and heme oxygenase-1 levels through the activation of Nrf2. We suggest that EPS has the potential to prevent several vascular diseases caused by oxidative stress.

Epalrestat increases intracellular glutathione levels in Schwann cells through transcription regulation.

Epalrestat (EPS), approved in Japan, is the only aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy. Here we report that EPS at near-plasma concentration increases the intracellular levels of glutathione (GSH), which is important for protection against oxidative injury, through transcription regulation. Treatment of Schwann cells with EPS caused a dramatic increase in intracellular GSH levels. EPS increased the mRNA levels of γ-glutamylcysteine synthetase (γ-GCS), the enzyme catalyzing the first and rate-limiting step in de novo GSH synthesis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that plays a central role in regulating the expression of γ-GCS. ELISA revealed that EPS increased nuclear Nrf2 levels. Knockdown of Nrf2 by siRNA suppressed the EPS-induced GSH biosynthesis. Furthermore, pretreatment with EPS reduced the cytotoxicity induced by H2O2, tert-butylhydroperoxide, 2,2'-azobis (2-amidinopropane) dihydrochloride, and menadione, indicating that EPS plays a role in protecting against oxidative stress. This is the first study to show that EPS induces GSH biosynthesis via the activation of Nrf2. We suggest that EPS has new beneficial properties that may prevent the development and progression of disorders caused by oxidative stress.

Glycolaldehyde induces cytotoxicity and increases glutathione and multidrug-resistance-associated protein levels in Schwann cells.

Schwann cell injury is observed in diabetic neuropathy. It is speculated that glycolaldehyde (GA), a precursor of advanced glycation end products (AGEs), contributes to the pathogenesis and development of diabetic neuropathy. Here, we demonstrated for the first time that GA at near-physiological concentration decreased the viability of rat Schwann cells. In contrast, methylglyoxal, glyoxal, and 3-deoxyglucosone, all of which are AGE precursors, had no effects on cell viability. It is well known that methylglyoxal causes oxidative damage. In the present study, however, GA failed to induce reactive oxygen species production in Schwann cells. The addition of glutathione (GSH) or N-acetyl-L-cysteine protected Schwann cells from the loss of viability induced by GA. Moreover, GA increased intracellular GSH level and γ-glutamylcysteine synthetase mRNA level. Flow cytometric analysis revealed that GA increased multidrug-resistance-associated protein 1 (MRP1) level as well. Moreover, we demonstrated that the knockdown of MRP1 with small interfering RNA (siRNA) enhanced the loss of cell viability induced by GA. Taken together, these findings suggest that MRP1, together with GSH, plays an important role in the GA-induced toxicity in Schwann cells.